Igf signaling control of chondrocyte hypertrophy in bone development and repair

 描述(申请人提供)：脊椎动物骨骼元素的发展需要精确控制细胞的生长和大小。脊椎动物的所有长骨都是通过软骨内成骨形成的，而软骨细胞前体形成了骨骼。在这个过程中，软骨细胞经历肥大，以拉长发育中的骨骼。最近，在这些软骨细胞中发现了三个不同的肥大阶段，并发现依赖胰岛素生长因子(IGF)的第三阶段的差异导致了骨骼长度的差异。这些发现打开了几个关于骨骼发育和修复以及导致骨骼元素缩短的病理学问题。IGF信号如何调节软骨细胞肥大仍然知之甚少，尤其是介导这一过程的下游靶点是什么。此外，在骨折修复过程中，软骨细胞比发育过程中观察到的更大。在这种情况下软骨细胞肥大的动力学还没有被研究，目前还不清楚这是否真的概括了发育或是否采用了替代机制。最后，多种遗传疾病会导致四肢长骨变短。尽管对其中一些疾病背后的遗传原因有所了解，但导致骨骼缩短的机制尚不清楚。因此，本研究的目的是研究IGF信号在软骨细胞发育和骨折修复过程中的肥大作用。最后，这项研究将研究导致四肢缩短的骨骼疾病小鼠模型中软骨细胞肥大的动力学。为了验证以下假设：(1)IGF信号通路下游转录靶点介导软骨细胞肥大。(2)骨折后的修复需要IGF依赖的软骨细胞肥大；(3)导致长骨缩短的遗传病理缺乏软骨细胞肥大的特定阶段。我提出了以下目标。具体目标1：确定介导软骨细胞肥大的IGF信号转导靶点。特异性目的2：探讨肥大软骨细胞在骨修复中的生长及对IGF信号的依赖性。具体目标3：评估导致肢体缩短的遗传性疾病小鼠模型中软骨细胞的大小和动力学。这些实验的成功完成将产生对IGF信号及其如何控制骨骼形态的更全面的了解。此外，这项研究的发现将拓宽我们对骨修复和再生的知识，并为发育性骨疾病提供潜在的治疗靶点。

 DESCRIPTION (provided by applicant): Development of the skeletal elements in vertebrates requires precise control over cell growth and size. All long bones of vertebrates are formed via endochondral ossification where bone forms from chondrocyte precursors. During this process, chondrocytes undergo hypertrophy in order to elongate the developing bone. Recently, three distinct phases of hypertrophy were discovered in these chondrocytes and differences in the Insulin growth factor (IGF)-dependent third phase were found to be responsible for differences in bone lengths. These findings open several questions on bone development and repair as well as pathologies that result in shortened skeletal elements. How IGF signaling regulates chondrocyte hypertrophy remains poorly understood, specifically what the downstream targets are that mediate this process. Further, during fracture repair, chondrocytes enlarge more than that observed during development. The dynamics of chondrocyte hypertrophy in this context have not been investigated and it remains unclear if this truly recapitulates development or if alternative mechanisms are employed. Finally, multiple genetic disorders result in shortened long bones of the limbs. Despite an understanding of the genetic cause behind some of these disorders, the mechanisms that result in shortened bones is not known. Therefore, the objectives of this study are to examine IGF signaling in chondrocyte hypertrophy during development and fracture repair. Finally, this study will investigate chondrocyte hypertrophy dynamics in mouse models for skeletal diseases that result in shortened limbs. In order to test the following hypotheses: (1) Downstream transcriptional targets of the IGF signaling pathway mediate hypertrophy in chondrocytes. (2) Repair following bone fracture requires IGF dependent chondrocyte hypertrophy and (3) Genetic pathologies that result in shortened long bones lack specific phases of chondrocyte hypertrophy. I propose the following aims. Specific Aim 1: Determine the targets of IGF signaling that mediate chondrocyte hypertrophy. Specific Aim 2: Investigate the growth of hypertrophic chondrocytes and IGF signaling dependence in repairing bone. Specific Aim 3: Assess chondrocyte size and dynamics in mouse models of genetic disorders that result in shortened limbs. The successful completion of these experiments will generate a more complete understanding of IGF signaling and how it controls skeletal morphology. Further, findings from this study will broaden our knowledge of bone repair and regeneration as well as suggest potential therapeutic targets for developmental bone diseases.